Dose, Safety, Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or With Alum Adjuvant, in Healthy Adults

VRC 317: A Phase I Randomized, Open-Label Clinical Trial to Evaluate Dose, Safety, Tolerability and Immunogenicity of a Stabilized Prefusion RSV F Subunit Protein Vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), Alone or With Alum Adjuvant, in Healthy Adults

Background:

Respiratory Syncytial Virus (RSV) is a virus that infects the lungs and breathing passages. Healthy adults who are infected generally have mild cold symptoms for a week or two. But it can also be serious, especially for infants and older adults. It can be spread by direct or indirect contact with respiratory secretions. Researchers want to study a new vaccine to prevent RSV.

Objective:

To see if a vaccine for RSV is safe and if it causes side effects.

Eligibility:

Healthy adults 18-50 years old

Design:

Volunteers were screened in a separate screening protocol.

Subjects had 13 visits over 1 year.

Some subjects received just vaccine. Some received vaccine mixed with alum adjuvant.

All subjects received their dose by injection in the upper arm. They received up to two doses, one at the beginning of the study and another 12 weeks later.

Subjects were monitored for 1 hour after injection and called to check on their safety 1 day after.

Subjects recorded their temperature and side effects for 7 days after each vaccination.

Subjects were provided with a thermometer to measure their temperature and a ruler to measure any changes if these occurred on their skin at the injection site.

At all visits, subjects were checked for health changes or problems. They may have had blood drawn.

At some visits, subjects had samples collected from their nose and mouth.

Study Overview

• Status: Completed
• Conditions: Respiratory Syncytial Virus
• Intervention / Treatment: Biological: VRC-RSVRGP084-00-VP; Other: Aluminum Hydroxide Suspension

Detailed Description

Study Design:

This is a Phase I, open-label, dose escalation study to evaluate the dose, safety, tolerability, and immunogenicity of VRC-RSVRGP084-00-VP vaccine alone or with alum adjuvant in a 2-injection regimen. The hypotheses are that the vaccine will be safe and tolerable for human administration, and will induce detectable immune response. The primary objective is to evaluate the safety and tolerability of the investigational vaccine at 3 dose levels administered alone or with alum adjuvant in healthy adults. Secondary objectives relate to humoral and cellular immunogenicity of the investigational vaccine regimen.

Product Description:

VRC-RSVRGP084-00-VP (DS-Cav1) was developed by VRC, NIAID and is composed of the respiratory syncytial virus (RSV) fusion (F) glycoprotein ectodomain assembled as a trimer stabilized in its prefusion native conformation with a foldon trimerization domain at the C-terminus and 4 internal mutations designated DS-Cav1 (4.1DHFR_RSVAF). The sequence is based on the RSV A2 strain from subtype A. The product was provided at a concentration of 0.5 mg/mL in 3 mL glass vials filled to 1.2 mL. Adjuvant was an aluminum hydroxide suspension (alum) provided in a sterile, pyrogen-free suspension at a concentration of 5 mg/mL in 3 mL glass vials filled to 0.7 mL. The alum dose was 500 mcg and was field mixed.

Subjects:

Healthy adult subjects ages 18-50 years

Study Plan:

Subjects were randomized into DS-Cav1 or DS-Cav1 plus alum in each dose during the study. Dose continuation and dose escalation evaluations occurred to ensure the safety data support proceeding to the higher doses. Subjects were evaluated for safety and immune responses through blood and mucosal sample collection at specified timepoints throughout the study.

VRC 317 Study Schema:

• Group: 1; Subjects: 15; Dose: 50mcg; Day 0: DS-Cav1; Week 12 [1]: DS-Cav1
• Group: 2; Subjects: 15; Dose: 50mcg; Day 0: DS-Cav1 + alum; Week 12 [1]: DS-Cav1 + alum
• Group: 3; Subjects: 15; Dose: 150mcg; Day 0: DS-Cav1; Week 12 [1]: DS-Cav1
• Group: 4; Subjects: 15; Dose: 150mcg; Day 0: DS-Cav1 + alum; Week 12 [1]: DS-Cav1 + alum
• Group: 5; Subjects: 15; Dose: 500mcg; Day 0: DS-Cav;1 Week 12 [1]: DS-Cav1
• Group: 6; Subjects: 15; Dose: 500mcg; Day 0: DS-Cav1 + alum; Week 12 [1]: DS-Cav1 + alum

All DS-Cav1 vaccinations were administered with needle and syringe into the deltoid muscle.

Total Planned Subjects: 90 (Up to 100 subjects could have been enrolled if needed to evaluate safety or immunogenicity.)

• [1] Week 12 dose: Optional for the last 5 subjects enrolled in each group who received the Day 0 injection and any additional subjects needed to evaluate safety or immunogenicity of a single injection.

Duration:

The study schedule required 13 clinic visits and a telephone contact after each injection.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

  1. 18 to 50 years of age.
  2. Willing and able to complete the informed consent process.
  3. Available for clinic visits through 44 weeks after enrollment.
  4. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
  5. Willing to donate blood and mucosal samples to be stored and used for future research.
  6. In good general health without clinically significant medical history.
  7. Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) less than or equal to 40 within the 56 days prior to enrollment. Laboratory criteria within 56 days prior to enrollment:
  8. White Blood Cell (WBC) and differential either within institutional normal range or accompanied by Principal Investigator (PI) or designee approval.
  9. Platelets = 125,000-500,000/mm^3.
  10. Hemoglobin within institutional normal range.
  11. Creatinine less than or equal to 1.1 x upper limit of normal (ULN).
  12. Alanine aminotransferase (ALT) less than or equal to 1.25 x ULN.

  13. Negative for HIV infection by an FDA approved method of detection.

      Criteria applicable to women of childbearing potential:

  14. Negative result on a human chorionic gonadotropin pregnancy test on day of enrollment before receiving study product.
  15. Agree to use effective means of birth control from at least 21 days before enrollment through 4 weeks after the last injection.
• EXCLUSION CRITERIA:

Criteria applicable to women of childbearing potential:

1. Breast-feeding or planning to become pregnant through 4 weeks after the last injection.

   Subject has received any of the following:

2. More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to enrollment or any within the 14 days prior to enrollment.
3. Blood products within 16 weeks prior to enrollment.
4. Live attenuated vaccines within 4 weeks prior to enrollment.
5. Inactivated vaccines within 2 weeks prior to enrollment.
6. Investigational research agents within 4 weeks prior to enrollment or planning to receive investigational products while on the study.
7. Current allergen immunotherapy with antigen injections, unless on maintenance schedule.

8. Current anti-tuberculosis(TB) prophylaxis or therapy.

   Subject has any of the following:

9. Serious reactions to vaccines that preclude receipt of study injections as determined by the investigator.
10. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.
11. Asthma that is not well controlled.
12. Diabetes mellitus (type I or II), with the exception of gestational diabetes.
13. Thyroid disease that is not well controlled.
14. Hypertension that is not well controlled.
15. Evidence of autoimmune disease or immunodeficiency.
16. Idiopathic urticaria within the past year.
17. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws.
18. Malignancy that is active or history of malignancy that is likely to recur during the study.
19. Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures that have not required treatment within the last 3 years.
20. Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen.
21. Psychiatric condition that precludes compliance with the protocol; past or present psychoses; or within 5 years prior to enrollment, a history of suicide plan or attempt.
22. Any medical, psychiatric, or social condition that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a subject s ability to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: DS-Cav1 (50 mcg); DS-Cav1 (50 mcg) administered intramuscularly (IM) by Needle/Syringe (Day 0 and Week 12*) *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.	Biological: VRC-RSVRGP084-00-VP; VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.; Other Names: DS-Cav1
Experimental: Group 2: DS-Cav1 (50 mcg) + alum; DS-Cav1 (50 mcg) + alum administered IM by Needle/Syringe (Day 0 and Week 12*) *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.	Biological: VRC-RSVRGP084-00-VP; VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.; Other Names: DS-Cav1; Other: Aluminum Hydroxide Suspension; Aluminum Hydroxide Suspension, alum, is an adjuvant.; Other Names: Alum
Experimental: Group 3: DS-Cav1 (150 mcg); DS-Cav1 (150 mcg) administered IM by Needle/Syringe (Day 0 and Week 12*) *The Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection, and for 5 additional subjects who were enrolled to evaluate the safety or immunogenicity of a single vaccine dose.	Biological: VRC-RSVRGP084-00-VP; VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.; Other Names: DS-Cav1
Experimental: Group 4: DS-Cav1 (150 mcg) + alum; DS-Cav1 (150 mcg) + alum administered IM by Needle/Syringe (Day 0 and Week 12*) *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.	Biological: VRC-RSVRGP084-00-VP; VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.; Other Names: DS-Cav1; Other: Aluminum Hydroxide Suspension; Aluminum Hydroxide Suspension, alum, is an adjuvant.; Other Names: Alum
Experimental: Group 5: DS-Cav1 (500 mcg); DS-Cav1 (500 mcg) administered IM by Needle/Syringe (Day 0 and Week 12*) *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.	Biological: VRC-RSVRGP084-00-VP; VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.; Other Names: DS-Cav1
Experimental: Group 6:DS-Cav1 (500 mcg) + alum; DS-Cav1 (500 mcg) + alum administered IM by Needle/Syringe (Day 0 and Week 12*) *To evaluate the safety or immunogenicity of a single vaccine dose, the Week 12 dose was optional for the last 5 subjects who enrolled in this group and received the Day 0 injection.	Biological: VRC-RSVRGP084-00-VP; VRC-RSVRGP084-00-VP is an investigational respiratory syncytial virus (RSV) vaccine.; Other Names: DS-Cav1; Other: Aluminum Hydroxide Suspension; Aluminum Hydroxide Suspension, alum, is an adjuvant.; Other Names: Alum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of the First Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the first study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of subjects reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).	7 days after the first product administration (Day 7)
Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of the Second Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the second study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of subjects reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).	7 days after the second product administration (Day 91)
Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of subjects reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).	7 days after each product administration
Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of the First Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the first study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of subjects reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).	7 days after the first product administration (Day 7)
Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of the Second Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after the second study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of subjects reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).	7 days after the second product administration (Day 91)
Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of Any Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Subjects recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Subjects were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of subjects reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).	7 days after each product administration
Number of Subjects With Abnormal Laboratory Measures of Safety	Any abnormal laboratory results recorded as unsolicited AEs are summarized. Safety laboratory parameters included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, white blood cell (WBC) and red blood cell (RBC) counts, and neutrophil, lymphocyte, monocyte, eosinophil and basophil percents and counts) and chemistry (alanine aminotransferase (ALT) and creatinine). Complete blood count (CBC) differential, platelet, creatinine and ALT results were collected at screening (≤ 56 days before enrollment), Day 0 prior to study product administration (baseline), and at Days 7, 28, 84, 91 and 112. Institutional laboratory normals as well as the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007 were used.	Day 0 through Day 308
Number of Subjects With One or More Unsolicited Non-Serious Adverse Events (AEs)	Unsolicited AEs and attribution assessments were recorded in the study database from receipt of the first study product administration through the visit scheduled for 28 days after each study product administration. At other time periods between study product administrations and when greater than 28 days after the last study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions that required ongoing medical management were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol. A subject with multiple experiences of the same event is counted once using the event of worst severity.	Day 0 through Day 28 after product administration
Number of Subjects With Serious Adverse Events (SAEs)	SAEs were reported from receipt of first study product administration through the last expected study visit at Day 308. The relationship between a SAE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol. A subject with multiple experiences of the same event is counted once using the event of worst severity.	Day 0 through Day 308
Number of Subjects Who Had Respiratory Syncytial Virus (RSV) Infection Following Product Administration	Respiratory Syncytial Virus (RSV) cases were recorded in the study database from receipt of the first study product administration through the last study visit.	Day 0 through Day 308

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Respiratory Syncytial Virus Subtype A (RSV A) Antigen-specific Neutralizing Antibody Geometric Mean Titers (GMTs) at 4 Weeks After the First Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Neutralizing antibody titers were determined against a reporter RSV A2 virus (RSV A), and were summarized using geometric mean 50% inhibitory concentration (IC50). Negative samples were reported and IC50 titers were calculated using half the limit of detection. Measurements were normalized to international units per milliliter.	4 weeks after the first product administration (Week 4)
Respiratory Syncytial Virus Subtype A (RSV A) Antigen-specific Neutralizing Antibody Geometric Mean Titers (GMTs) at 4 Weeks After the Second Product Administration of DS-Cav1 Alone or With Alum Adjuvant	Neutralizing antibody titers were determined against a reporter RSV A2 virus (RSV A), and were summarized using geometric mean 50% inhibitory concentration (IC50). Negative samples were reported and IC50 titers were calculated using half the limit of detection. Measurements were normalized to international units per milliliter.	4 weeks after the second product administration (Week 16)

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Grace L Chen, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Ruckwardt TJ, Morabito KM, Graham BS. Determinants of early life immune responses to RSV infection. Curr Opin Virol. 2016 Feb;16:151-157. doi: 10.1016/j.coviro.2016.01.003. Epub 2016 Mar 15.
• Ngwuta JO, Chen M, Modjarrad K, Joyce MG, Kanekiyo M, Kumar A, Yassine HM, Moin SM, Killikelly AM, Chuang GY, Druz A, Georgiev IS, Rundlet EJ, Sastry M, Stewart-Jones GB, Yang Y, Zhang B, Nason MC, Capella C, Peeples ME, Ledgerwood JE, McLellan JS, Kwong PD, Graham BS. Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med. 2015 Oct 14;7(309):309ra162. doi: 10.1126/scitranslmed.aac4241.
• Graham BS, Modjarrad K, McLellan JS. Novel antigens for RSV vaccines. Curr Opin Immunol. 2015 Aug;35:30-8. doi: 10.1016/j.coi.2015.04.005. Epub 2015 Jun 10.
• Crank MC, Ruckwardt TJ, Chen M, Morabito KM, Phung E, Costner PJ, Holman LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Kumar A, Chang LA, Moin SM, Hill JP, DiPiazza AT, Schwartz RM, Kueltzo L, Cooper JW, Chen P, Stein JA, Carlton K, Gall JG, Nason MC, Kwong PD, Chen GL, Mascola JR, McLellan JS, Ledgerwood JE, Graham BS; VRC 317 Study Team. A proof of concept for structure-based vaccine design targeting RSV in humans. Science. 2019 Aug 2;365(6452):505-509. doi: 10.1126/science.aav9033.
• Ruckwardt TJ, Morabito KM, Phung E, Crank MC, Costner PJ, Holman LA, Chang LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Lin B, Bailer R, Chen M, Ortega-Villa AM, Nguyen T, Kumar A, Schwartz RM, Kueltzo LA, Stein JA, Carlton K, Gall JG, Nason MC, Mascola JR, Chen G, Graham BS; VRC 317 study team. Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial. Lancet Respir Med. 2021 Oct;9(10):1111-1120. doi: 10.1016/S2213-2600(21)00098-9. Epub 2021 Apr 14.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2017
• Primary Completion (Actual): October 3, 2019
• Study Completion (Actual): October 3, 2019

Study Registration Dates

• First Submitted: February 9, 2017
• First Submitted That Met QC Criteria: February 9, 2017
• First Posted (Actual): February 10, 2017

Study Record Updates

• Last Update Posted (Actual): October 23, 2020
• Last Update Submitted That Met QC Criteria: October 21, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Immune Response; Respiratory Syncytial Virus; Vaccine-Mediated Protection; Neutralizing Antibody; Antibody Response
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Gastrointestinal Agents; Adjuvants, Immunologic; Antacids; Aluminum Hydroxide
• Other Study ID Numbers: 170058; 17-I-0058 (Other Identifier: NIH NIAID IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No